Author
Konstanze Doehner
Bio: Konstanze Doehner is an academic researcher from University of Ulm. The author has contributed to research in topics: Myeloid leukemia & Leukemia. The author has an hindex of 7, co-authored 22 publications receiving 1791 citations.
Topics: Myeloid leukemia, Leukemia, Progenitor cell, Tyrosine kinase, Mutation
Papers
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TL;DR: It is shown that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis, establishing the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
Abstract: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction2, 3. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC2, 3 and the polymerase-associated factor complex (PAFc)4, 5, are associated with the BET family of acetyl-lysine recognizing, chromatin ‘adaptor’ proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
1,388 citations
Mayo Clinic1, University of Paris2, VU University Amsterdam3, Erasmus University Rotterdam4, Leiden University5, Maastricht University6, Autonomous University of Madrid7, University of Freiburg8, University of Ulm9, University of Basel10, University of Angers11, University of Bordeaux12, Joseph Fourier University13, Guy's and St Thomas' NHS Foundation Trust14, British Hospital15, University of Puerto Rico16, Pompeu Fabra University17, University of Barcelona18, University of Florence19, University of Pavia20, Karolinska Institutet21, Uppsala University22
TL;DR: The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptoms study to date.
Abstract: Purpose Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. Patients and Methods The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Results MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P < .001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) f...
321 citations
Journal Article•
TL;DR: Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features.
182 citations
TL;DR: The prognostic role of polymorphisms in three GST genes (GSTP1/M1/T1) in a large patient cohort of the German Austrian Acute Myeloid Leukemia Study Group is studied, finding the favorable impact of GSTP1*105 Val on RFS seems to be restricted to the subgroup of patients exhibiting a normal karyotype.
Abstract: Glutathione S-transferases (GSTs) are phase II detoxification enzymes involved in the metabolism of carcinogens and anticancer drugs, known also to interact with kinase complexes during oxidative or chemical stress-induced apoptosis. We were interested whether their polymorphic variants may account for differences in outcome of patients with acute myeloid leukemia (AML) following chemotherapy. We studied the prognostic role of polymorphisms in three GST genes (GSTP1/M1/T1) in a large patient cohort of the German Austrian Acute Myeloid Leukemia Study Group, treated according to prospective multicenter clinical trials (AML HD98A: 254 patients; AML HD98-B: 100 patients), with a median follow-up of 46 months. Looking at short-term adverse drug reactions, homozygous carriers of the GSTP1*105 Val allele had a faster neutrophil and platelet recovery (P=0.002 and 0.02, respectively) and a reduced need of red cell and platelet transfusions (P=0.01 and 0.03, respectively). Response to induction chemotherapy did not vary according to GST polymorphisms. Multivariable Cox regression models revealed a significant better relapse-free (RFS) and overall survival for the GSTP1(*)105 Val (P=0.003 and 0.03, respectively), whereas GSTT1 and GSTM1 genotypes had no significant impact. The favorable impact of GSTP1(*)105 Val on RFS seems to be restricted to the subgroup of patients exhibiting a normal karyotype.
34 citations
Mayo Clinic1, Paris Diderot University2, VU University Medical Center3, Erasmus University Rotterdam4, Loyola University Medical Center5, Hospital Universitario La Paz6, University of Ulm7, University Hospital of Basel8, French Institute of Health and Medical Research9, University of Grenoble10, Guy's and St Thomas' NHS Foundation Trust11, University of Puerto Rico12, Foundation Center13, University of Florence14, University of Pavia15, Uppsala University16, Peking Union Medical College17, Imperial College London18
TL;DR: In this article, the authors evaluated the role of improvement in MPN-SAF TSS quartiles as potential thresholds to assess symptomatic response to therapy, and found that patients with higher TSS scores were more likely to have a history of prior thrombosis.
13 citations
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TL;DR: The basic principles behind DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting are presented and the evidence suggesting that their misregulation can culminate in cancer is highlighted.
2,501 citations
TL;DR: This work investigates how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition ofThe MYC oncogene in multiple myeloma (MM), and finds that super-enhancers were found at key oncogenic drivers in many other tumor cells.
2,292 citations
TL;DR: A personal perspective on the development of epigenetics, from its historical origins to what is defined as 'the modern era of epigenetic research', is provided.
Abstract: Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. Here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as 'the modern era of epigenetic research'. We primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.
1,764 citations
TL;DR: Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
Abstract: The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
1,396 citations
TL;DR: Bromodomains are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks, and a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4 is uncovered.
1,346 citations